title: Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory.
abstract: Ras and Rap small GTPases are important for synaptic plasticity and memory. However, their roles in homeostatic plasticity are unknown. Here, we report that polo-like kinase 2 (Plk2), a homeostatic suppressor of overexcitation, governs the activity of Ras and Rap via coordination of their regulatory proteins. Plk2 directs elimination of Ras activator RasGRF1 and Rap inhibitor SPAR via phosphorylation-dependent ubiquitin-proteasome degradation. Conversely, Plk2 phosphorylation stimulates Ras inhibitor SynGAP and Rap activator PDZGEF1. These Ras/Rap regulators perform complementary functions to downregulate dendritic spines and AMPA receptors following elevated activity, and their collective regulation by Plk2 profoundly stimulates Rap and suppresses Ras. Furthermore, perturbation of Plk2 disrupts Ras and Rap signaling, prevents homeostatic shrinkage and loss of dendritic spines, and impairs proper memory formation. Our study demonstrates a critical role of Plk2 in the synchronized tuning of Ras and Rap and underscores the functional importance of this regulation in homeostatic synaptic plasticity.
authors.affiliation: Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20057-1464, USA.
authors.forename: Kea Joo
authors.initials: KJ
authors.lastname: Lee
authors.forename: Yeunkum
authors.initials: Y
authors.lastname: Lee
authors.forename: Aaron
authors.initials: A
authors.lastname: Rozeboom
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Lee
authors.forename: Noriko
authors.initials: N
authors.lastname: Udagawa
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Hoe
authors.forename: Daniel T S
authors.initials: DT
authors.lastname: Pak
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049229:Dendritic Spines / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006624:Hippocampus / Q000378:metabolism; D008568:Memory / Q000502:physiology*; D051379:Mice; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020668:rap GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D018091:Receptors, AMPA; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C444640:serum-inducible kinase; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D020668:rap GTP-Binding Proteins; D018631:ras Proteins